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In this study, we investigated the anti\u2010cooperative characteristics of TFP binding to CaM and the effect of TFP on the CaM\u2010Fas interaction from both structural and thermodynamic perspectives using combined molecular dynamics simulations and binding free energy analyses. We studied the interactions of different numbers of TFP molecules with CaM and explored the effects of the resulting conformational changes in CaM on CaM\u2010Fas binding. Results from these analyses showed that the number of TFP molecules bound to CaM directly influenced \u03b1\u2010helix formation and hydrogen bond occupancy within the \u03b1\u2010helices of CaM, contributing to the conformational and motion changes in CaM. These changes affected CaM binding to Fas, resulting in secondary structural changes in Fas and conformational and motion changes of Fas in CaM\u2010Fas complexes, potentially perturbing the recruitment of Fas\u2010associated death domain for DISC formation. The computational results from this study reveal the structural and molecular mechanisms that underlie the role of the CaM antagonist, TFP, in regulation of CaM\u2010Fas binding and Fas\u2010mediated DISC formation in a concentration\u2010dependent manner. Proteins 2011; \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.23081","type":"journal-article","created":{"date-parts":[[2011,5,16]],"date-time":"2011-05-16T16:36:22Z","timestamp":1305563782000},"page":"2543-2556","source":"Crossref","is-referenced-by-count":14,"title":["Trifluoperazine regulation of calmodulin binding to Fas: A computational study"],"prefix":"10.1002","volume":"79","author":[{"given":"Di","family":"Pan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yabing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay M.","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhua","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,6,7]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81874-7"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1053\/hupa.2001.22769"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1692"},{"key":"e_1_2_7_5_2","first-page":"4791","article-title":"Fas expression and function in normal and malignant breast cell lines","volume":"56","author":"Keane MM","year":"1996","journal-title":"Cancer Res"},{"key":"e_1_2_7_6_2","first-page":"2936","article-title":"Fas\/APO\u20101 gene transfer for human malignant glioma","volume":"55","author":"Weller M","year":"1995","journal-title":"Cancer Res"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.108.130542"},{"key":"e_1_2_7_8_2","first-page":"1382","article-title":"Frequent mutations of Fas gene in thyroid lymphoma","volume":"61","author":"Takakuwa T","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65434-X"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.7.1063"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/356314a0"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90013-6"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7539157"},{"key":"e_1_2_7_14_2","volume-title":"Primary immunodeficiency diseases: a molecular and genetic approach","author":"Puck J","year":"1999"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-8-41"},{"key":"e_1_2_7_16_2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.5858\/2005-129-481-ROAIC","article-title":"Regulators of apoptosis in cholangiocarcinoma","volume":"129","author":"Jhala NC","year":"2005","journal-title":"Arch Pathol Lab Med"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10516"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v7.i6.860"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2000.18192"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510300618"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65113-9"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.35.20643"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1986.4.6.994"},{"key":"e_1_2_7_24_2","first-page":"249","article-title":"Inhibition of lung metastasis by a calmodulin antagonist. 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